A thrombus is the result of processes which initiate the coagulation cascade. It is composed of an aggregation of platelets enmeshed in a polymeric network of fibrin. This process is normally initiated as a consequence of tissue injury and has the effect of slowing or preventing blood flow in a vessel. Etiological factors which are not directly related to tissue injury, such as atherosclerotic plaque, inflammation of the blood vessels (phlebitis) and septicemia, may also initiate thrombus formation. In some instances, the inappropriate formation of a thrombus, and subsequent decrease in blood flow, may have pathological consequences, such as stroke, pulmonary embolism and heart disease.
Platelets play a major role in thrombus formation. Current antithrombotic therapy employs agents that modify the platelet/endothelial cell arachidonate-prostaglandin system, such as prostacyclin analogues, cyclooxygenase inhibitors, thromboxane synthesis inhibitors and thromboxane receptor antagonists; and anti-coagulants, such as heparin. These agents inhibit one or both of two discernible phases of platelet aggregation. The primary phase, which is a response to chemical stimuli, such as ADP (adenosine diphosphate), collagen, epinephrine or thrombin, causes initial activation of the platelets. This is followed by a secondary phase, which is initiated by the platelets themselves, and is characterized by thromboxane A.sub.2 (TxA.sub.2) synthesis and the release of additional ADP from platelet storage granules, which further activates platelets.
Prostacyclin, also called prostaglandin I.sub.2 (PGI2), and stable PGI.sub.2 analogues inhibit both the primary and secondary phases of platelet aggregation. However, use of such analogues has been associated with undesirable changes in blood pressure. See Aiken, et al., Prostaglandins, 19, 629-43 (1980).
Cyclooxygenase inhibitors and thromboxane synthetase inhibitors act to block the production of TxA.sub.2. TxA.sub.2 antagonists block the effects of TxA.sub.2 by binding the TxA.sub.2 receptor. These therapies act only upon the secondary stage of platelet activation. Use of cyclooxygenase inhibitors has been associated with ulcerogenesis and an adverse effect upon prostacyclin synthesis.
Heparin prevents the activation of fibrinogen by thrombin and thereby prevents the activation of the GPIIb-IIIa receptor by thrombin. This inhibits only the primary phase of platelet aggregation and has little effect upon activation of platelets by other means, such as collagen, ADP and epinephrine.
Cyclooxygenase inhibitors, prostaglandin analogues and heparin all inhibit platelet aggregation indirectly by inhibiting the primary or secondary phase of platelet/fibrinogen activation. There is therefore a need for selective therapeutic products which block platelet aggregation directly, whether it arises from the primary or secondary phase of platelet activation.
Platelet aggregation is believed to be mediated primarily through the GPIIb-IIIa platelet receptor complex, which is also called the fibrinogen receptor. Von Willebrand factor, a plasma protein, and fibrinogen are able to bind and crosslink GPIIb-IIIa receptors on adjacent platelets and thereby effect aggregation of platelets. Preventing the binding and crosslinking of GPIIb-IIIa receptors is believed to be method of inhibiting platelet aggregation.
GPIIb-IIIa is a member of a larger class of receptor proteins, called integrins, which mediate adhesive functions. Fibronectin, vitronectin and thrombospondin are proteins which have also been demonstrated to bind to GPIIb-IIIa. Fibronectin is found in plasma and as a structural protein in the intracellular matrix. Binding between the structural proteins and GPIIb-IIIa may function to cause platelets to adhere to damaged vessel walls, and aid in arresting blood flow from a damaged vessel. It is desirable to be able to interrupt the interaction of platelets with fibrinogen, selectively, without having a major effect upon their interactions with the structural proteins.
Peptide fragments of human plasma fibronectin and synthetic peptides containing an RGD (single letter amino acid code for Arg--Gly--Asp) sequence which promote cell attachment and enhance phagocytosis are disclosed in U.S. Pat. Nos. 517,686, 4,589,881, 4,661,111 and U.S. Pat. No. 4,614,517. Linear and cyclic peptides containing an RGD sequence have also been reported in WO 89/05150 (PCT US88/04403). Peptides which contain an RGD sequence have been reported to inhibit platelet aggregation. Nievelstein et al. Thromb. and Hemostasis, 58, 2133 (1987) have reported that -RGDS- peptides inhibit thrombin induced aggregation and adhesion of platelets to fibronectin, and may interact through the GPIIb-IIIa complex. U.S. Pat. No. 4,683,291 discloses peptides containing Arg and Lys and an -RGD- sequence which inhibit binding of fibrinogen to platelets and inhibit platelet aggregation. A disadvantage of these peptides is their poor stability in plasma and their low potency. EP 0 275 748 discloses linear tetra- to hexapeptides and cyclic hexa- to octapeptides which bind to the GPIIb-IIIa receptor and inhibit platelet aggregation. Other linear and cyclic peptides, the disclosure of which are incorporated herein by reference, are reported in EP-A 0 341 915. Inhibitors of the fibrinogen receptor which are not based upon natural amino acid sequences are disclosed in EP-A 0 372,468 and EP-A 0 381 033. However, there remains a need for fibrinogen receptor antagonists which are potent and show a high selectivity for the fibrinogen receptor relative to other matrix proteins.
The instant invention provides novel 1,4-diazocine compounds which have increased selectivity toward the fibrinogen receptor.